This invention relates to trans(.+-.) or trans(-)-octahydropyrimido[4,5-g]quinolines of the formulas ##STR1## wherein R is H, CN and C.sub.1 -C.sub.3 alkyl or allyl; R.sup.1 is H, OH, SH, O-C.sub.1 -C.sub.3 alkyl, S-C.sub.1 -C.sub.3 alkyl or NH.sub.2 ; R.sup.2 is H, OH or NH.sub.2 with the proviso that R.sup.1 can only be NH.sub.2 when R.sup.2 is OH or NH.sub.2 ; and acid addition salts thereof made from non-toxic acids. Formula I is named as a trans-(.+-.)-6-substituted-2,4-permissibly-substituted-5,5a,6,7,8,9,9a,10- octahydropyrimido[4,5-g]quinoline and formula II is the corresponding trans-(-)-enantiomer.
Preferred subgroups of compounds represented by I or II above include:
(a) compounds in which R is C.sub.1 -C.sub.3 alkyl;
(b) compounds in which R is n-propyl;
(c) compounds in which R.sup.2 is H; and
(d) compounds in which R.sup.1 is SH or S-C.sub.1 -C.sub.3 alkyl.
The compounds represented by formulas I and II absorb ultraviolet light with absorption peaks in the range 265-350 mu, (which range encompasses the UVA--280-300 mu range--) and are therefore potentially useful as sunscreen agents. The compounds are also useful as intermediates, as will be more fully developed hereinafter.
Compounds according to I or II in which R.sup.1 is SH or S-C.sub.1 -C.sub.3 alkyl and R.sup.2 is H are prepared by reacting thiourea or an S-C.sub.1 -C.sub.3 alkyl isothiourea with a compound of the formula III or IV ##STR2##
Compounds according to I and II wherein R.sup.2 is H and R.sup.1 is OH are prepared by acidic hydrolysis of a trans-(.+-.) or trans-(-)-2-C.sub.1 -C.sub.3 alkylthio-6-C.sub.1 -C.sub.3 alkyl or allyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]quinoline. The product of this reaction, a 2-OH derivative, can be readily alkylated by standard etherification reactions; e.g., dimethylsulfate and base, to yield the 2-C.sub.1 -C.sub.3 alkoxy derivatives; e.g., a 2-methoxy derivative, according to I or II.
Compounds according to I or II in which R.sup.1 is NH.sub.2 and R.sup.2 is OH are prepared by reacting a 1-alkyl or allyl-6-oxo-7-alkoxycarbonyldecahydroquinoline (furnished by the procedure of Schaus, Huser and Booher, Ser. No. 535,519, filed Sept. 26, 1983, whereby a trans-(.+-.) or trans-(-)-6-oxo-1-C.sub.1 -C.sub.3 alkyl or allyldecahydroquinoline is reacted with a dialkyl carbonate in the presence of sodium hydride in an inert mutual solvent, with a guanidine salt. After work-up of the reaction mixture, the 2-amino-4-hydroxy derivative thus formed is isolated by standard means.
Compounds according to I or II in which both R.sup.1 and R.sup.2 are NH.sub.2 are prepared by cyclizing the usual trans-(.+-.) or trans-(-)-1-substituted-6-oxodecahydroquinoline with cyanoguanidine in a high boiling mutual inert solvent such as CARBITOL--see Modest et al., J. Org. Chem., 30, 1837 (1965). When R.sup.1 and R.sup.2 are H, a different cyclization reaction is employed to join the pyrimidine ring to a 1-C.sub.1 -C.sub.3 alkyl or allyl decahydroquinoline nucleus. The procedure of Boger et al. J. Org. Chem., 47, 2673 (1982) was adapted to the specific synthetic goal. This procedure involves the reaction of a cyclic ketone with pyrrolidine to form an enamine (Formula V or VI below), reaction of which with 1,3,5-triazine yields an unsubstituted pyrimidine ring fused to the decahydroquinoline. ##STR3## wherein R is C.sub.1 -C.sub.3 alkyl or allyl.
An illustrative reaction from Boger is that of cyclohexanone with pyrrolidine to form a 1-pyrrolidino-1-cyclohexene which, on treatment with 1,3,5-triazine yields tetrahydroquinazoline. In our reaction, the trans-(.+-.) or trans-(-)-1-C.sub.1 -C.sub.3 alkyl or allyl-6-oxodecahydroquinoline is the starting ketone which forms the enamine with pyrrolidine.
While compounds according to I and II in which R is C.sub.1 -C.sub.3 alkyl or allyl are the primary products of this invention, those compounds in which R is H or CN are not only UV absorbers but are also intermediates for the preparation of compounds carrying a different alkyl group (from that of the 6-oxodecahydroquinoline starting material) or an allyl group. For example, if it is desired to prepare a compound according to I or II in which R is allyl, it is possible (depending on the nature of the R.sup.1 and R.sup.2 substituents) to replace the R alkyl group with CN (using CNBr), and then to remove the CN group by hydrolysis to yield compounds wherein R is H. This secondary amine derivative can then be allylated as with allyl chloride or can be reductively alkylated with an aldehyde or can be alkylated with a C.sub.1 -C.sub.3 alkyl halide to yield a compound according to I or II having an allyl group or a different alkyl at N-6. Incidentally, it is not necessary to replace an N-methyl with a different alkyl group in order for the above process to be useful. For example, it is possible to replace a CH.sub.3 group with a .sup.13 CH.sub. 3 containing an isotopically-tagged carbon. Preferably, however, because of the reactivity of SH and OH groups at C-2 in I or II to CNBr, the interchange of groups on the quinoline nitrogen should take place prior to ring closure; i.e., at the 6-oxodecahydroquinoline stage. In this procedure, a trans-(.+-.) or trans-(-)-1-methyl-6-oxodecahydroquinoline, for example, is transformed to the 1-cyano compound--see Bach et al., J. Med. Chem., 23, 481 (1980) or U.S. Pat. No. 4,198,415. Acidic hydrolysis or hydrogenolysis of this compound by the methods of Titus and Bach, Ser. No. 535,522, filed Sept. 26, 1983, yields trans-(.+-.) or trans-(-)-6-oxodecahydroquinoline. This secondary amine can then be allylated or realkylated possibly with a tagged alkyl, using allyl or alkyl halides to prepare the desired intermediate trans-(.+-.) or trans-(-)-1-allyl or alkyl-6-oxodecahydroquinoline. The above procedures are clearly extremely useful in preparing the difficult-to-obtain N-allyl derivatives because the best procedures for obtaining the 2-alkyl-6-oxodecahydroquinolines involves multiple reduction or hydrogenation procedures, and an allyl group would not survive all of these synthetic steps.